In the field of cancer therapy, immunotherapies that increase the strength of immune responses against tumors have become an increasingly important tool. In the case of T cells, the robustness of the anti-tumor response is regulated by a balance between co-stimulatory and inhibitory signals which are referred to as “immune checkpoints.” In their normal function, immune checkpoints are involved in maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. In disease, it is believed that tumors co-opt certain immune checkpoint pathways to generate and maintain immune resistance against T cells that are specific for tumor antigens.
Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. The interaction between the programmed death 1 (PD-1) receptor and its ligands PD-L1 and PD-L2 has shown promise as a target for checkpoint blockade. Engagement of PD-1 by its ligands, PD-L1 and PD-L2, induces an inhibitory signal resulting in reduced T-cell proliferation, cytokine production, and cytotoxic activity, while blockade of PD-1 or its ligands promotes antitumor activity. Additionally, PD-1 reportedly plays an important role in regulating functional exhaustion of virus-specific CD8+ T cells during chronic viral infections. In vivo blockade of PD-1 has been demonstrated to restore the function of exhausted CD8+ T cells during chronic viral infections, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV).
Antagonistic antibodies to PD-1 known as nivolumab (Opdivo) and pembrolizumab (Keytruda) have received FDA approval for the treatment of a number of cancers, including melanoma, non-small-cell lung cancer, and renal cell carcinoma, and a number of additional clinical trials are ongoing for additional indications. That said, the use of antagonistic PD-1 antibodies does have limitations. In one study, less than 30 percent of melanoma and lung cancer patients responded to treatment and at this time it is not possible to predict with certainty which patients will respond to a PD-1 antibody.
A non-limiting set of characteristics which can be indicative of a useful PD-1 antagonistic antibody include one or more of: specific binding to a PD-1-expressing cell with a nanomolar EC50, and Kd, inhibition of binding between PD-1 and its ligands with a nanomolar IC50, promotion of antigen-specific T-cell responses in vitro, no mediation of antibody-dependent cell-mediated cytotoxicity (ADCC) in T cells, and no mediation of complement-dependent cytotoxicity (CDC) in T cells.